PROJECT SUIVIMARY (See instructions): The Signal Transduction (ST) Research Program promotes studies aimed at understanding of signal transduction pathways in carcinogenesis and cancer progression. In the long run, this will facilitate development of effective cancer therapeutics and optimal matching of targeted drugs to individual patients for maximal therapeutic impact The Signal Transduction Research Program was established in the previous cycle of this CCSG based on two major premises. First, the majority of human cancers are driven by dysregulation of cellular pathways that normally link hormone-dependent signaling to fundamental cellular processes relevant to cancer including regulation of cell division, protection from apoptosis, tumor angiogenesis, lineage restrictions, and changes associated with cancer progression. Second, signal transduction molecules, including peptide growth factors, receptor kinases, non-receptor kinases, and components of pathways that they regulate, have emerged as important targets for new cancer therapies. The portfolio of effective new cancer therapies that attack oncogenic signaling products and their subservient pathways has expanded to encompass dozens of US FDA-approved pharmaceuticals, with many more in the clinical developmental pipeline. These drugs, when, employed with patient selection based on genetic or functional criteria, have great impact, but as yet are only appropriate for a minority of cancer patients. Moreover, with increased experience in the clinic, a major practical issue has emerged: the rapid development of resistance to these agents, even in patients who initially responded dramatically. Hence, an important new area of investigation in the ST Research Program is the mechanisms of drug resistance, and the means to anticipate and defeat them. The 31 ST program members are drawn from 14 departments at Yale College and Yale Medical School. They include faculty investigating all aspects of signal transduction research related to cancer, including work on receptor signaling mechanisms, signaling pathways, cytoskeleton, cell polarity, intracellular protein trafficking, and integrated signaling networks. Recruitment of six new faculty with research programs centered on cancer biology has increased cancer focus. Since the last CCSG cycle, ST program members have published 412 (2006-2012) cancer related papers, of which 24 (6%) were intra-programmatic and 105 (25%) inter-programmatic. The total cancer research funding of the ST Program is $6.7M annual direct costs ($10.4M total costs, of which $8.4M is peer-reviewed, and $3.7 M NCI-funded).